WO2001007431A2

WO2001007431A2 - Benzothiophene derivatives

Info

Publication number: WO2001007431A2
Application number: PCT/US2000/016334
Authority: WO
Inventors: Stephen Richard Baker; David Bleakman; Carmen Dominguez Fernandez; Almudena Rubio Esteban; Esteban Dominguez Manzanares
Original assignee: Eli Lilly And Company
Priority date: 1999-07-21
Filing date: 2000-07-18
Publication date: 2001-02-01
Also published as: AU6050500A; WO2001007431A3

Abstract

Compounds of formula (I) in which R1, R2, Y, L and Z have the meanings given in the specification are GluR6 antagonists useful for the treatment of disorders of the central nervous system.

Description

BENZOTHIOPHENE DERIVATIVES

The present invention relates to certain benzothiophene derivatives which are useful as pharmaceuticals . More particularly it relates to a new pharmaceutical use for novel and known benzothiophene derivatives, to novel benzothiophene derivatives, to a process for preparing the novel benzothiophene derivatives and to a pharmaceutical composition comprising benzothiophene derivatives. L-Glutamate mediates excitatory neurotransmission in the mammalian central nervous system through its action at glutamate receptors. There are two broad classes of gluta ate receptors, known as the ionotropic glutamate receptors and the metabotropic glutamate receptors . Within the class of ionotropic glutamate receptor are three classes, known as the N-methyl-D-aspartate (NMDA) , (R,S)-2- amino-3- (3-hydroxy-5-methyl-isoxazol-4-yl)propanoate (AMPA) and kainate (KA) receptors. Molecular biological studies have established that AMPA receptors are composed of subunits (GluRl-4) that can assemble to form functional channels. Five kainate receptors, classified as either high affinity (KAl and KA2 ) or low affinity (GluR5, GluRβ and GluR7) kainate receptors have been identified. (Bleakman et al , Molecular Pharmacology, 1996, Vol. 49, No. 4, pgs. 581- 585 and Hollmann, M. , and Heinemann, S., Cloned Glutamate Receptors, Ann. Rev. Neurosci. 1994, 17: 31-108).

It has now been found that certain benzothiophene derivatives, some of which are known and some of which are novel, antagonize the action of L-Glutamate at GluRβ receptors. As such, they are useful for the treatment of disorders of the central nervous system, as described in more detail hereinafter.

Many benzothiophene derivatives are known in the art . United States patent number 5,632,898 discloses the compound 2-[ (4-phenyl-l-piperazinyl) acetyl] -5-chloro-3- methylbenzo [b] thiophene. No use for this compound is disclosed. International patent application publication number WO 96/16052 discloses certain l-aryl-3-piperazin-l-ylpropanones useful for the treatment of neurodegenerative diseases, such as Alzheimer's Disease (by preventing or decreasing the production of abnormally phosphorylated paired helical filament epitopes associated with neurofibrillary tangles) , neoplastic disease, and bacterial and fungal infections. 1- (5-chloro-3-methylbenzo [b] thien-2-yl] -3- [4- (phenylmethyl) -1- piperazinyl] -1-propanone; 1- (3, 5-dimethylbenzo [b] thien-2- yl] -3- [4- (phenylmethyl) -1-piperazinyl] -1-propanone are specifically disclosed.

European patent application publication number EP-A1- 0169012 discloses certain benzothiophene derivatives useful as anti-diarrhoeal agents. A sub-group of compounds is disclosed having at the 3-position a phenyl group which is unsubstituted or substituted by halo, Cι-C alkoxy or C₂-C₅ alkoxycarbonyl and at the 2-position a group of formula

-X-(CH₂)_n-NR³R⁴ in which X is -CH=CH- or -(CH₂) -; n is 1, 2, 3 or 4 and either R³ and R⁴ are each independently H or Ci-C alkyl, or R³ and R⁴ together with the nitrogen atom to which they are attached form a 1-pyrrolidinyl or piperidino group. Several compounds belonging to this sub-group are specifically disclosed where X is -CH=CH- and R³ and R⁴ each represents methyl . United States patent number 4,542,145 discloses certain N- [ (1H-1, 2 , 4-triazol-l-yl) alky] Iheteroarylcarboxamides as inhibitors of thromboxane synthase. Specific compounds disclosed include, for example, 3-chloro-N- [3- (1H-1, 2 , 4- triazol-1-yl) ethyl ]benzo [b] thiophene-2-carboxamide. Chemical Abstracts registry number 95638-77-0 discloses the compound 3-chloro-N- [3- (2-ethyl-lH-imidazol-l- y1 ) propylbenzo [b] thiophene-2-carboxamide .

United States patent number 4,489,089 discloses certain N- [ω- (lH-imidazol-1-yl) alkyl] amides having activity as thromboxane synthase inhibitors. The amides include certain 3-halo-N- (lH-imidazol-1-yl) alkylbenzo [b] thiophene-2- carboxa ides, such as 3-chloro-N- [4- (lH-imidazol-1- yl) butyl] benzo [b] thiophene-2-carboxamide . Fiziol. Akt. Veshchestra, 8, 49-51, 1976 discloses certain aminoalkyl 3-chloro-benzo [b] thiophene-2- carboxylates , such as 3- (dimethylamino)propyl 3- chlorobenzo [b] thiophene-2-carboxylate; 2- (diethylamino) ethyl 3-chlorobenzo[b] thiophene-2-carboxylate and 2-dimethyl- amino) ethyl 3-chlorobenzo [b] thiophene-2-carboxylate.

United States patents numbers 3,646,047 and 3,734,915 disclose certain 3-alkyl and 3-halo N- (tert-aminoalkyl) derivatives of benzo [b] thiophene-2-carboxamide having CNS activity, in particular as tranquilizers, CNS depressants, hypnotics and muscle relaxants . 3-Chloro-N- [2- (4-phenyl-l- piperazinyl) ethyl] benzo [b] thiophene-2-carboxamide and 3,6- dichloro-N- [2- (4-phenyl-l-piperazinyl) ethyl]benzo [b] - thiophene-2-carboxamide are specifically disclosed.

German patent application publication number DE 1936721 discloses certain 3-alkyl and 3-halo N-morpholinoalkyl) - benzo [b] thiophene-2-carboxamides as tranquilizers, antidepressants, hypnotics and muscle relaxants.

Accordingly, the present invention provides the use of a compound of general formula :-

in which:

R¹ represents a halogen atom, a (1-6C) alkyl, halo (1-6C) alkyl or (1-6C) alkylthio group, or a phenyl group which is unsubstituted or substituted by one or two substituents selected independently from a halogen atom, a (1-4C) alkyl group and a (1-4C) alkoxy group;

R² represents a hydrogen atom, a halogen atom, a (1-4C) alkyl group or a (1-4C) alkoxy group;

Y represents COCHR³, COO, CONH or CH=CH;

R³ represents a hydrogen atom, a (1-4C) alkyl group, a phenyl group or a group of formula - ^a-Z^a in which ^a is as defined for L and Z^a is as defined for Z; L represents a bond or (1-4C) alkylene; and

Z represents :

(i) -NR⁴R⁵, in which each of R⁴ and R⁵ independently represents (1-4C) alkyl;

(ii) a group of formula

in which R represents phenyl, phenyl (1-4C) alkyl or hydroxy (2-4C) alkyl ; (iii) a group of formula

in which R⁷ represents hydrogen or (1-4C) alkyl;

(iv) -NHR⁸ in which R⁸ represents pyridyl or (CH₂)_nNR⁹R¹⁰ in which n is an integer of from 1 to 4 and R⁹ and R¹⁰ each independently represents ( 1-4C) alkyl;

(v) pyridyl

(vi) a group of formula

in which A- represents an anion; (vii) a group of formula

in which R¹¹ represents phenyl, L^b represents a bond or (1- 4C)alkylene and R¹² represents phenyl which is unsubstituted or substituted by one or two substituents selected from a halogen atom, a (1-4C) alkyl group and a (1-4C) alkoxy group; or

(viii) OR¹³ in which R¹³ represents (1-4C) alkanoyl; or a pharmaceutically acceptable salt thereof, provided that when Y represents COO or CONH, L does not represent a bond, for the manufacture of a medicament for the treatment of a condition indicating treatment with a GluR6 antagonist.

The present invention also provides a method of antagonising the action of L-glutamate at GluRβ receptors in a warm blooded mammal requiring such treatment, which comprises administering to said mammal an effective amount of a compound of general formula I, or a pharmaceutically acceptable salt thereof as defined hereinabove.

As described hereinabove, compounds of formula I have been found to be antagonists of L-glutamate at GluRβ receptors . They have further been found to be non- competitive antagonists. In other words, their antagonist effect has been found to be unaffected by increasing concentration of agonist. Furthermore, it has been found that their action is both use-dependent and voltage- dependent. In particular, it has been found that the compounds exhibit a slow onset of inhibition which develops with agonist activation of the receptor and reverses at a rate dependent upon agonist activation. Inhibition has been observed at hyperpolarised (negative) membrane potentials, but not depolarised (positive) potentials.

A variety of physiological functions have been shown to be subject to influence by excessive or inappropriate stimulation of excitatory amino acid transmission. The formula I compounds of the present invention are believed, through their action as GluR6 antagonists, to have the ability to treat a variety of neurological disorders in mammals associated with this condition, including acute neurological disorders such as cerebral deficits subsequent to cardiac bypass surgery and grafting, stroke, cerebral ischemia, spinal cord lesions due to trauma or infarction/ischaemia or inflammation, head trauma, perinatal hypoxia, cardiac arrest, and hypoglycemic neuronal damage, and chronic neurological disorders, such as Alzheimer's disease, Huntington's Chorea, inherited ataxias, amyotrophic lateral sclerosis, AIDS-induced dementia, ocular damage and retinopathy, cognitive disorders, Parkinson's Disease, drug- induced Parkinsonism and essential tremor. The present invention also provides methods for treating these disorders which comprises administering to a patient in need thereof an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof .

The formula I compounds of the present invention are also believed, through their action as GluR6 antagonists, to have the ability to treat a variety of other neurological disorders in mammals that are associated with glutamate dysfunction, including muscular spasms, convulsions (such as epilepsy) , spasticity, migraine headache, cluster headache, chronic daily headache, urinary incontinence, psychosis,

(such as schizophrenia or bipolar disorder) , post traumatic stress disorder, depression, drug tolerance and withdrawal (such as alcohol, nicotine, opiates and benzodiazepines) , drug intoxication, metabolic derangement, anxiety and related disorders, emesis, brain edema, pain (acute and chronic, neuropathic or retractable, post traumatic pain) , and tardive dyskinesia. Therefore, the present invention also provides methods for treating these disorders which comprise administering to a patient in need thereof an effective amount of the compound of formula I, or a pharmaceutically acceptable salt thereof.

The term "treating" for purposes of the present invention, includes prophylaxis, amelioration or elimination of a named condition once the condition has been established.

The term "patient" for purposes of the present invention is defined as any warm blooded animal such as, but not limited to, a mouse, guinea pig, dog, horse, or human. Preferably, the patient is human. It will be appreciated that the compounds of formula (I) may contain one or more asymmetric carbon atoms. Accordingly, the compounds of the invention may exist in and be isolated in enantiomerically pure form, in racemic form, or in a diastereoisomeric mixture. The present invention includes all such forms .

As used herein, the term (1-6C) alkyl group means a straight or branched alkyl group containing from 1 to 6 carbon atoms. It includes the term (1-4C) alkyl. Examples of particular values for a (1-βC) alkyl group are methyl, ethyl, propyl, isopropyl, butyl and isobutyl .

Examples of particular values for halogen atom are fluorine, chlorine and bromine atoms. Examples of particular values for a (1-4C) lkoxy group are methoxy and ethoxy.

An example of a halo (1-βC) alkyl group is bromomethyl.

An example of a (1-6C) alkylthio group is methylthio.

Examples of particular values for a (1-4C) alkylene group are methylene, ethylene, propylene and butylene.

In the compounds of formula I, R¹ preferably represents chlorine, methyl, ethyl, propyl, butyl, bromomethyl, or phenyl .

R² preferably represents hydrogen. R³ preferably represents a hydrogen atom, an ethyl group, a phenyl group or a group of formula -L^a-Z^a in which L^a represents methylene and Z^a represents dimethylamino .

L preferably represents a bond, methylene, ethylene or propylene . R⁴ and R⁵ preferably each represent methyl .

R⁶ preferably represents phenyl, benzyl or 2- hydroxyethyl .

R⁷ preferably represents hydrogen or methyl .

A^' preferably represents a halogen ion, such as bromide .

Examples of values for R⁸ are 2-pyridyl, 3 -pyridyl, 4- pyridyl and 2- (dimethylamino) ethyl .

R⁹ and R¹⁰ preferably each represent methyl .

L^b preferably represents a bond or methylene. Examples of values for R¹² are phenyl and 3,4- dichlorophenyl .

R¹³ preferably represents ethanoyl . Z preferably represents dimethylamino; l-(4- phenyl)piperazinyl; 1- (4-benzyl)piperazinyl ; l-(4-(2- hydroxy) ethyl ) piperazinyl ; 1-imidazolyl ; l-(2- methyl) imidazolyl; 1- (4-methyl) imidazolyl ; l-(5- methyl) imidazolyl; 2-pyridylamino; 3-pyridylamino; 4- pyridylamino; 2- (dimethylamino) ethylamino; 2-pyridyl; 3- pyridyl; 4-pyridyl; 4-aminopyridinium halide; 1,3- diphenylureido; 3-benzyl-l-phenylureido; 3- (3,4- dichlorophenyl) -1-phenylureido or acetoxy

The present invention includes pharmaceutically acceptable salts of the formula (I) compounds. These salts can exist in conjunction with an acidic or basic portion of the molecule and can exist as acid addition, primary, secondary, tertiary, or quaternary ammonium, alkali metal, or alkaline earth metal salts. Generally, the acid addition salts are prepared by the reaction of an acid with a compound of formula (I) . The alkali metal and alkaline earth metal salts are generally prepared by the reaction of the hydroxide form of the desired metal salt with a compound of formula (I) .

Acid addition salts are preferably the pharmaceutically acceptable, non-toxic addition salts with suitable acids, such as those with inorganic acids, for example hydrochloric, hydrobromic, nitric, sulphuric or phosphoric acids, or with organic acids, such as organic carboxylic acids, for example, glycollic, maleic, hydroxymaleic, fumaric, malic, tartaric, citric, salicyclic, o-acetoxybenzoic, or organic sulphonic, 2-hydroxyethane sulphonic, toluene-p-sulphonic, or naphthalene-2-sulphonic acid. 10

In addition to pharmaceutically-acceptable salts, other salts are included in the invention. They may serve as intermediates in the purification of compounds or in the preparation of other, for example pharmaceutically- acceptable, acid addition salts, or are useful for identification, characterisation or purification.

Certain compounds of formula I are believed to be novel, and are provided as a further aspect of the invention.

Accordingly, the present invention provides a compound of general formula :-

in which:

R¹ represents a halogen atom, a (1-6C) alkyl, halo (1-6C) alkyl or (l-βC)alkylthio group, or a phenyl group which is unsubstituted or substituted by one or two substituents selected independently from a halogen atom, a (1-4C) alkyl group and a (1-4C) alkoxy group;

Y represents COCHR³, COO, CONH or CH=CH;

R³ represents a hydrogen atom, a (1-4C) alkyl group, a phenyl group or a group of formula -L^a-Z^a in which L^a is as defined for L and Z^a is as defined for Z;

L represents a bond or (1-4C) alkylene; and

Z represents:

(i) -NR⁴R⁵, in which each of R⁴ and R⁵ independently represents (1-4C) alkyl ; (ii) a group of formula

in which R⁶ represents phenyl, phenyl (1-4C) alkyl or hydroxy (2-4C) alkyl ; (iii) a group of formula

in which R⁷ represents hydrogen or (1-4C) alkyl; (iv) -NHR⁸ in which R⁸ represents pyridyl or (CH₂)_nNR⁹R¹⁰ in which n is an integer of from 1 to 4 and R⁹ and R¹⁰ each independently represents (1-4C) alkyl; (v) pyridyl (vi) a group of formula

in which A- represents an anion ; (vii ) a group of formula

in which R represents phenyl, L represents a bond or (1- 4C)alkylene and R¹² represents phenyl which is unsubstituted or substituted by one or two substituents selected from a halogen atom, a (1-4C) alkyl group and a (1-4C) alkoxy group; or (viii) OR¹³ in which R¹³ represents (1-4C) alkanoyl; or a pharmaceutically acceptable salt thereof, provided that : -

(a) when Y represents COO or CONH, L does not represent a bond;

(b) when Y represents -CH=CH- and Z represents dimethylamino, R¹ does not represent an unsubstituted or substituted phenyl group;

(c) when Y represents CONH and R¹ represents a halogen atom, Z does not represent a group of formula

(d) the compound of formula I is not selected fro :-

2- [ (4-phenyl-l-piperazinyl) acetyl] -5-chloro-3- methylbenzo [b] thiophene ; 1- (5-chloro-3-methylbenzo [b] thien-2-yl] -3- [4- (phenylmethyl)

1-piperazinyl] -1-propanone;

1- (3, 5-dimethylbenzo [b] thien-2-yl] -3- [4- (phenylmethyl) -1- piperazinyl] -1-propanone;

3-chloro-N- [3- (2-ethyl-lH-imidazol-l-yl)propylbenzo [b] - thiophene-2-carboxamide;

3- (dimethylamino) propyl 3-chlorobenzo [b] thiophene-2- carboxylate ;

2- (diethylamino) ethyl 3-chlorobenzo [b] thiophene-2- carboxylate; 2-dimethylamino) ethyl 3-chlorobenzo [b] thiophene-2- carboxylate;

3-chloro-N- [2- (4-phenyl-l-piperazinyl) ethyl] benzo [b] - thiophene-2-carboxamide;

3 , 6-dichloro-N- [2- (4-phenyl-l-piperazinyl) ethyl ] benzo [b] - thiophene-2-carboxamide and 2- (3-dimethylamino-l-oxopropyl] -3-methyl-5-chloro- benzothiophene .

The invention also comprises a process for preparing a novel compound according to formula (I) , or a salt thereof which comprises: (a) reacting a compound of formula

in which X represents a leaving atom or group, with the appropriate amine, or for a compound of formula I in which Z represents OR ,13 , the appropriate anhydride; reacting a compound of formula

III with an N,N-dimethylmethyleneaπιmonium halide;

(c) for a compound of formula I in which Y represents COR³, R³ represents L^a-Z^a, L and L^a each represents ethylene and Z and Z^a each represents dimethylamino, reacting a compound of formula III with tetramethyldiaminomethane; (d) for a compound of formula I in which Z represents a group of formula

reacting a compound of formula

IV with an isocyanate of formula

CN-L^bR¹² V (e) for a compound of formula I in which Y represents CH=CH, Z represents pyridyl and L represents a bond, reacting a compound of formula

VI with the appropriate methylpyridine;

(f) for a compound of formula I in which Y represents CONH, reacting a compound of formula

VII or a reactive derivative thereof, with an amine of formula

HN-L-Z VIII (g) for a compound of formula I in which Y represents COOH, reacting a compound of formula VII or a reactive derivative thereof with a compound of formula 15

HO-L-Z IX (h) for a compound of formula I in which Y is COCH, L is CH₂ and Z is a group of formula

reacting a compound of formula

X with a compound of formula

XI followed, if desired, by forming a salt.

In process (a) according to the invention, the leaving atom or group represented by X¹ may be, for example, a halogen atom, such as a bromine atom, or a dimethylamino grou .

When X¹ represents a halogen atom, the reaction is conveniently performed at a temperature of from 0 to 100 °C in the presence of a base, such as sodium hydrogen carbonate. Convenient solvents include nitriles, such as acetonitrile . 16

When X¹ represents a dimethylamino group, the reaction is conveniently performed at a temperature of from 0 to 100 °C in the presence of an acid, such as hydrogen chloride. Convenient solvents include alcohols, such as ethanol.

Compounds of formula II in which X¹ represents a halogen atom may be prepared by reacting a compound of formula

XII with a compound of formula

X³-Y-L-X¹

XIII in which X³ represents a leaving atom or group, such as a chlorine atom. The reaction is conveniently performed at a temperature in the range of from 0 to 150 °C in the presence of a Lewis acid, such as boron trifluoride etherate. Convenient solvents include halogenated hydrocarbons, such as dichloromethane.

Compounds of formula II in which X¹ represents a dimethylamino group may be prepared by the method of process (b) .

In process (b) according to the invention, the N,N- dimethylammonium halide may be, for example, the chloride. The reaction is conveniently performed at a temperature in the range of from 0 to 150 °C. Convenient solvents include ■nitriles, such as acetonitrile.

Process (c) according to the invention is conveniently performed at a temperature in the range of from 0 to 100 °C and in the presence of an acid, such as acetic acid. Convenient solvents include ethers, such as tetrahydrofuran. Process (d) according to the invention is conveniently performed at a temperature in the range of from 0 to 100 °C. Convenient solvents include halogenated hydrocarbons, such as chloroform. After the reaction has been completed, any excess isocyanate is conveniently removed using a scavenging agent, such as aminomethyl polystyrene.

Process (e) according to the invention is conveniently performed at a temperature in the range of from 50 to 180 °C and in the presence of a base, such as sodium acetate. Convenient solvents include anhydrides, such as acetic anhydride.

The starting compound of formula VI may conveniently be prepared by reacting the appropriate 2-unsubstituted benzothiophene with N,N-dimethylformamide in the presence of a strong base, such as butyl lithium and at a temperature of about -80 to 0°C. Convenient solvents include ethers such as tetrahydrofuran.

In process (f) according to the invention, the reactive derivative of the compound of formula VII may be, for example, an acid halide, such as the chloride, which nay conveniently be generated in si tu , for example by reacting a compound of formula VII with oxalyl chloride. The reaction with the amine is conveniently performed at a temperature in the range of from -10 to 100 °C and in the presence of a base, such as triethylamine . Convenient solvents include ethers, such as tetrahydrofuran.

The staring material of formula VII is conveniently prepared by oxidising a compound of formula VI, for example using Jones ' reagent . Process (g) according to the invention is conveniently performed at a temperature in the range of from 0 to 150 °C Convenient solvents include ethers, such as tetrahydrofuran. Process (h) according to the invention is conveniently performed at a temperature in the range of from 0 to 100 °C. 18

Convenient solvents include halogenated hydrocarbons, such as chloroform.

The starting materials of formula X may be prepared by reacting a compound of formula

XIII with an anhydride, such as acetic anhydride, in the presence of a base, such as sodium acetate. The reaction is conveniently performed at a temperature of from 50 to 120 °C.

The present invention further provides the novel starting materials described herein.

The particular effective amount or dose of compound administered according to this invention will of course be determined by the particular circumstances surrounding the case, including the compound administered, the route of administration, the particular condition being treated, and similar considerations. The compounds can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, or intranasal routes. Alternatively, the compound may be administered by continuous infusion. A typical daily dose will contain from about 0.01 mg/kg to about 100 mg/kg of the active compound of this invention. Preferably, daily doses will be about 0.05 mg/kg to about 50 mg/kg, more preferably from about 0.1 mg/kg to about 25 mg/kg.

The activity of compounds according to the invention may be demonstrated in the following test, which involves the electrophysiological characterization of test compounds using HEK293 cells stably expressing human GluRδ . The cells may be obtained as described in Hoo, K. H., et al . , Receptors Channels 1994, 2, 327-337. In the test, cells are dissociated by trituration and plated out onto poly-L-lysine coated (10 μg/ml) glass coverslips. Whole-cell voltage clamp recordings (Vh = - 70mV) are made using the tight seal whole cell configuration of the patch-clamp technique (Hamill et al . , (1981) Pflϋgers Arch., 391: 85-100). Glass fragments of coverslips with adherent cells are placed in a perfusion chamber, pre-incubated with 250μg/ml conconavalin A to remove agonist-induced desensitization, and rinsed with buffer of composition: 138mM NaCl, 5mM CaCl₂, 5mM KC1, ImM MgCl₂, lOmM HEPES and lOmM glucose, pH of 7.5 with NaOH

(osmolality 315 mosm/kg) . The recording pipette solutions contain 140mM CsCl, ImM MgCl₂, 14mM HEPES (N-[2- hydroxyethyl] -piperazin-N' - [2-ethanesulfonic acid]) and 15mM BAPTA ( 1, 2-bis (2-aminophenoxy) ethane-N,N,N' ,N' , -tetraacetic acid ), pH of 7.2 with CsOH (osmolality 295 mosm/kg).

Experiments were performed at ambient temperature (20-22 °C) and recorded on either a List EPC-7 or an Axopatch ID amplifier.

Cells were superfused with solution containing agonist (ImM kainate) in buffer and steady state current values obtained. Agonist in the presence of compound was then applied and the reduction in the inward current from control kainate-induced current measured. The reduction in current produced by the compound was assessed at steady state. Recovery of control currents elicited by kainate (lμM) was established by repeat application of kainate to the cells via the external solution. The compound tested were evaluated for use-dependency. The recovery from compound inhibition of kainate-induced current was dependent upon the rate of repeat kainate application following antagonist inhibition of currents. In addition, outward currents measured by voltage-clamping at positive potentials (+70mV) were not inhibited by the compounds whereas inward currents were.

All of the compounds exemplified herein, and the compound 2- (3-dimethylamino-l-oxopropyl] -3-methyl-5-chloro- benzothiophene, have been found to show activity in this test at a concentration of 30 micromolar or lower.

The compounds of the present invention are preferably formulated prior to administration. Therefore, another aspect of the present invention is a pharmaceutical formulation comprising a compound of formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The present pharmaceutical formulations are prepared by known procedures using well-known and readily available ingredients. In making the formulations of the present invention, the active ingredient will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier, and may be in the form of a capsule, sachet, paper, or other container. When the carrier serves as a diluent, it may be a solid, semi-solid, or liquid material which acts as a vehicle, excipient, or medium for the active ingredient. The compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments containing, for example, up to 10% by weight of active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.

Some examples of suitable carriers include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum, acacia, calcium phosphate, alginates, tragacanth, gelatin, 21

calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water syrup, methyl cellulose, methyl and propyl hydroxybenzoates, talc, magnesium stearate, and mineral oil. The formulations can additionally include lubricating agents, wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents, or flavoring agents. Formulations of the invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art .

The formulations are preferably formulated in a unit dosage form, each dosage containing from about 5 mg to about 500 mg, more preferably about 25 mg to about 300 mg of the active ingredient. The term "unit dosage form" refers to a physically discrete unit suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutically acceptable carrier.

The following formulation examples are illustrative only and are not intended to limit the scope of the invention in any way.

Formulation 1

Hard gelatin capsules are prepared using the following ingredients :

Quantity (mg/capsule)

Active Ingredient 250

Starch, dried 200 Magnesium stearate 10

Total 460 mg

The above ingredients are mixed and filled into hard gelatin capsules in 460 mg quantities.

23

Formulation 2

Tablets each containing 60 mg of active ingredient are made as follows:

Active Ingredient 60 mg

Starch 45 _mg Microcrystalline cellulose 35 mg

Polyvinylpyrrolidone 4 mg

Sodium carboxymethyl starch 4.5 mg

Magnesium stearate 0.5 mg

Talc 1 mg

Total 150 mg

The active ingredient, starch, and cellulose are passed through a No . 45 mesh U.S. sieve and mixed thoroughly. The solution of polyvinylpyrrolidone is mixed with the resultant powders which are then passed through a No . 14 mesh U.S. sieve. The granules so produced are dried at 50 ;C and passed through a No. 18 mesh U.S. sieve. The sodium carboxymethyl starch, magnesium stearate, and talc, previously passed through a No . 60 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 150 mg.

The following Examples illustrate the invention. In the Examples, Et₂0 signifies diethylether, AcOEt signifies ethyl acetate, MeOH signifies methanol, THF signifies tetrahydrofuran, DMF signifies dimethylformamide, and Jones Reagent signifies a solution of 1. Og of Na₂Cr₂0₇.2H₂0 and 1.34 g of sulfuric acid in H₂0 (total volume 5 ml. Example 1 2- (5-dimethylamino-l-oxopentyl) -3-methylbenzothiop βne hydrochloride a) 2- [5-bromo-2-oxopentyl] -3 -methylbenzothiophene To a solution of 3-methylbenzothiophene (1 g, 6.74 mmol) in 10 mL of dichloromethane was added 5-bromopentanoyl chloride (6.74 mmol) and BF₃.OEt₂ (6.74 mmol). The reaction mixture was heated at 80^s C for 4 hours and then quenched with a saturated NaHC0₃ solution (25 mL) and extracted with dichloromethane (2 x 30 mL) . The combined organic phases were dried (MgS0 ) and evaporated to dryness giving an oil which was purified by column chromatography (hexane/ethyl acetate: 15/1). ^XH NMR (CDC1₃) 7.89 ( , 2H) , 7.47 (m, 2H) , 3.47 (t, J = 7.0 Hz, 2H) , 2.97 (t, J = 7.0 Hz, 2.77 (s, 3H) , 2.10-1.80 (m, J = 7.0 Hz, 2H) . b) 2- (5-dimethylamino-l-oxopentyl) -3-methylbenzothiophene hydrochloride

To a solution of the product of step a) (0.32 mmol) in acetonitrile (5 mL) , was added dimethylamine hydrochloride (3.2 mmol), NaHC0₃ (3.8 mmol) and Nal (0.064 mmol). The reaction mixture was heated under reflux for 5 hours and then water (10 mL) was added and the product was extracted with CH₂C1₂ (2 x 20 mL) . The combined organic phases were dried (MgS04) and evaporated to dryness giving an oil which was treated with a saturated HC1 solution in ether.

Evaporation of the ether yielded the title compound as a white solid. Yield: 70%. M.p. 211^» C. 1H NMR (MeOH-d⁴) 8.0- 7.80 (m, 2H) , 7.55-7.36 (m, 2H) 3.3-3.0 (m, 4H) , 2.90 (s, 6H) , 2.72 (s, 3H) . 1.90-1.70 (m, 4H) . Example 2

2- [5- (4-aminopyridinium) -1-oxopentyl] -

3-methylbenzothiophene bromide

The title compound was obtained using the procedure described in Example lb) but using as amine 4-amino pyridine. The crude product obtained after evaporation of the dichloromethane was recrystallized from methanol. 90% yield. 1H NMR (MeOH-d⁴) 8.13 (d, J = 7.5 Hz, 2H) , 7.90 (m, 2H) , 7.50 (m, 2H) , 6.84 (d, J = 7.5 Hz, 2H) , 4.20 (t, J = 7.0 Hz, 2 H) , 3.05 (t, 7.0 Hz, 2H) , 2.72 (s, 3H) , 2.05-1.70 (m, 4H) .

Example 3 2- [5- (dimethylaminoethylamino) -1-oxopentyl] -3- methylbenzothiophene dihydrochloride

The title compound was obtained using the same procedure as described in Example lb) , but using N,N- dimethylethylendia ine. ^XH NMR (MeOH-d⁴) 8.05 (m, 2H) , 7.65 (m, 2H) , 3.60-2.70 (m, 8H) , 3.10 (s, 6H) , 2.85 (s, 3H) , 2.50-2.20 (m, 2H) , 2.10-1.90 (m, 2H) .

Example 4 2- [4- (dimethylamino) -1-oxobutyl] -3-methylbenzothiophene hydrochloride a) 2- [4-bromo-2-oxobutyl] -3-methylbenzothiophene.

The title compound was obtained as described in Example la), but using 4-bromobutanoylchloride. ^XH NMR (CDC1₃) 7.89 ( , 2H) , 7.47 (m, 2H) , 3.57 (t, J = 7.0 Hz, 2H) , 3.17 (t, J = 7.0 Hz, 2.80 (s, 3H) , 2.35 (quint, J = 7.0 Hz, 2H) . b) 2- [4- (dimethylamino) -1-oxobutyl] -3-methylbenzothiophene hydrochloride

The title compound was obtained from the product of step a) as described in Example lb). ^XH NMR (MeOH-d⁴) 7.90 (m, 2H) , 7 . 45 (m, 2H) , 3 . 35 -2 . 90 (m, 4H ) , 2 . 92 ( s , 6H ) , 2 . 70 ( s , 3H) , 2 . 15 (m, 2H) .

Example 5 2- [4- (N- (4-amino)pyridinium) -1-oxobutyl] -3- methylbenzothiophene bromide

The title compound was prepared using the compound obtained in the Example 4a) by the method described in the Example lb) and using 4-aminopyridine as the amine. M.p. > 250² C. ^XH NMR (MeOH-d⁴) 8.12 (d, J = 6.8 Hz, 2H) , 7.95 (m, 2H) , 7.50 (m, 2H) , 6.82 (d, J = 6.8 Hz, 2H) , 4.24 (t, J = 7.0 Hz, 2H) , 2.73 (s, 3H) , 2.26 (t, J = 7.0 Hz, 2H.

Example 6 2- [3-dimethylamino-2-phenyl-l-oxopropyl] -3- methylbenzothiophene hydrochloride a) 2- [2-phenyl-l-oxoethyl] -3-methylbenzothiophene. The title compound was obtained by the method of

Example la) , but using 2-phenylethanoyl chloride. ¹H NMR (CDC1₃) 7.90 (m, 2H) , 7.45 (m, 2H) , 4.22 (s, 2H) , 2.72 (s, 3H) . b) N,N-dimethylmethyleneammonium chloride.

To a cooled solution (0² C) of tetramethyl- diaminomethane (10 g, 98 mmol) in diethyl ether (100 mL) was added dropwise acetyl chloride (7 mL, 98 mmol) . The salt precipitated as a white solid. The salt was quickly filtered and dried in vacuo . It can be stored under argon (very hygroscopic) . c) 2- [3-dimethylamino-2-phenyl-1-oxopropyl] -3- methylbenzothiophene hydrochloride

A suspension of the N,N-dimethylmethyleneammonium chloride (2.12 g, 22.8 mmol) from step b) and the product of step a) (25.1 mmol) in acetonitrile (20 mL) was heated at 85^s C for 1 hour. The precipitate was filtered, washed with acetonitrile and dried in vacuo . M.p. 165² C. ¹H NMR (MeOH- d⁴) 7.85- 7.75 (m, 2H) , 7.50-7.26 (m, 2H) , 5.52 (dd, J = 3.3 and 8.0 Hz, 1H) , 4.1 (dd, J = 8.0 and 12.8 Hz, 1H) , 3.29 (dd, J = 3.3 and 12.8 Hz, 1H) , 2.77 (s, 3H) , 2.74 (s, 6H) .

Example 7

2- [3- (N-imidazolyl) -2-ethyl-l-oxopropyl] -3- methylbenzothiophene hydrochloride a) 2- [1-oxobutyl] -3-methylbenzothiophene. The title compound was obtained as described in Example la), but using butanoyl chloride. ^λE NMR (CDC1₃) 7.90 (m, 2H) , 7.45 (m, 2H) , 2.92 (t, J = 7.1 Hz, 2H) , 2.75 (s, 3H) , 1.80 (sext, J = 7.1 Hz, 2H) , 1.15 (t, J = 7.1 Hz, 3H) . b) 2- [3-dimethylamino-2-ethyl-l-oxopropyl] -3- methylbenzothiophene hydrochloride

The title compound was prepared from the product of step a) using the procedure described in Example 6c) . M.p. 173-4² C. ^λE NMR (MeOH-d⁴) 8.0 (m, 2H) , 7.55 (m, 2H) , 3.82 (dd, J = 10.0 and 12.1 Hz, 1H) , 3.70 (m, 1H) , 3.29 (dd, J = 2.7 and 12.1 Hz, 1H) , 2.91 (s, 6H) , 2.81 (s, 6H) . 2.0-1.7 (m, 2H) , 1.00 (t, J =7.4 Hz, 3H) . c) 2- [3- (N-imidazolyl) -2-ethyl-l-oxopropyl] -3-methylbenzothiophene hydrochloride

A solution of the product of step b) (2 mmol) and imidazole in ethanol (10 mL) was heated under reflux overnight. Then, the solvent was evaporated and the residue was partitioned between 10% NaOH solution (20 mL) and dichloromethane (20 mL) . The aqueous solution was extracted with dichloromethane (2 x 20 mL) , dried (MgS0₄) and evaporated in vacuo . The oily residue was treated with a saturated HC1 solution in ether, evaporated to dryness and the resulting solid was filtered and washed with ether to afford the title compound. M.p. 144-6² C. ^XH NMR (MeOH-d⁴) 9.01 (s, 1H) 8.00-7.85 (m, 2H) , 7.70 (s, 1H) , 7.62-7.85 (m, 28

3H) , 4.73 (dd, J = 9.8 and 13.7 Hz, 1H) , 4.47 (dd, J = 4.5 and 14.7 Hz, 1H) 3.87 (m, 1H) , 2.73 (s, 3H) , 2.10-1.70 (m, 2H) 1.03 (t, J =7.4 Hz, 3H) .

Example 8

2- [3- (5-methyl-N-imidazolyl) -1-oxopropyl] -3- methylbenzothiophene hydrochloride and 2- [3- (4-methyl-N-imidazolyl) -1-oxopropyl] -3- methylbenzothiophene hydrochloride a) 2- [3-dimethylamino-l-oxopropyl] -3-methylbenzothiophene hydrochloride .

The title compound was obtained by the method of Example 6 c) from 3-methyl-2-acetylbenzothiophene. ¹H NMR (MeOH-d⁴) 7.95 (m, 2H) , 7.50 (m, 2H) , 3.57 (s, 4H) , 2.97 (s, 6H) , 2.80 (s, 3H) . b) 2- [3- (5-methyl-N-imidazolyl) -1-oxopropyl] -3- methylbenzothiophene hydrochloride and 2- [3- ( 4-methyl-N- imidazolyl) -1-oxopropyl] -3-methylbenzothiophene hydrochloride . The title mixture of compounds was obtained as a 6/1 mixture using the same procedure as described in Example 7c). -H NMR (MeOH-d⁴) 8.91 (s, 0.15H), 8.84 (s, 0.85 H) , 7.79 (m, 2H) , 7.43-7.15 (m, 3H) , 4.53 ( , 2H) , 3.56 (m, 2H) , 2.60 (s, 3H) , 2.40 (s, 0.45H), 2.25 (s, 2.55H).

Example 9 2- [3- (2-methyl-N-imidazolyl) -1-oxopropyl] -3- methylbenzothiophene hydrochloride The title compound was prepared from the compound of Example 8a) using the method described in Example 8b) and using 2-methylimidazole . M.p. 222² C. ^XH NMR (MeOH-d⁴) 7.79 (m, 2H) , 7.55-7.30 (m, 4H) , 4.46 (t, J = 5.4 Hz, 2H) , 3.59 (t, J = 5.4 Hz, 2H) , 2.70 (s, 3H) , 2.67 (s, 3H) . 29

Example 10 2- [3- (4-pyridyl) amino-1-oxopropyl] -3-methylbenzothiophene dihydrochloride

The title compound was obtained from the compound of Example 8a) using the method described in Example 8b) and using 4-aminopyridine. M.p. 215² C. ¹H NMR (MeOH-d⁴) 8.07 (d, J = 7.5 Hz, 2H) , 7.89 (m, 2H) , 7.55-7.30 (m, 2H) , 6.90 (d, J = 7.5 Hz, 2H) , 3.75 (t, J = 7 Hz, 2H) , 3.39 (t, J = 7 Hz, 2H) , 2.70 (s, 3H) .

Example 11 2- [3- (N-4-aminopyridinium) -1-oxopropyl] -3- methylbenzothiophene bromide

The title compound was obtained from the product of Example 8a) by the method described in Example 8b) and using 4-aminopyridine as the amine, acetonitrile as solvent and performing the reaction for two hours. The white precipitate obtained was filtered and washed with acetonitrile to afford the title compound. M.p. 208-9² C. ^TH NMR (MeOH-d⁴) 8.22 (d, J = 7.6 Hz, 2H) , 7.00-7.80 (m, 2H) , 7.6-7.4 (m, 2H) , 6.82

(d, J = 7.6 Hz, 2H) , 4.55 (t, J = 6.1 Hz, 2H) , 3.66 (t, J = 6.1 Hz, 2H) , 2.73 (s, 3H) .

Example 12 2- [3- (3-pyridyl) amino-1-oxopropyl] -3-methylbenzothiophene dihydrochloride

The title compound was obtained from the product of Example 8a) by the method described in Example 8b) and using 3-aminopyridine. M.p. 168-70² C. ^λH NMR (MeOH-d⁴) 8.09 (d, J = 2.1 Hz, 2H) , 7.95 (m, 3H) , 7.8-7.65 (m, 2H) , 7.60-7.40 (m, 2H) , 3.66 (t, J = 6.1 Hz, 2H) , 3.37 (t, J = 6.1 Hz, 2H) , 2.77 (s, 3H) . Example 13 2- [bis (dimethylaminomethyl) acetyl] -3-methylbenzothiophene dihydrochloride

To a stirred solution of 2-acetyl-3-methyl- benzothiophene (1.05 mmol) and acetic acid (10.5 mmol) in THF (2 mL) was slowly added tetramethyldiaminomethane (TMDAM, 10.5 mmol) . The mixture was stirred at room temperature for 18 hours and then it was diluted with dichloromethane (20 mL) and washed with water (2 x 20 mL) and a saturated solution of NaHC0₃. The organic layer was dried (MgS0 ) and evaporated to dryness. The crude product was treated with a saturated solution of HCl in ether and then the solvent was evaporated yielding the title compound as a white solid, 60% yield. M.p. 157-159² C. ^XH NMR (MeOH- d⁴) 8.05 (m, 2H) , 7.60 (m, 2H) , 4.28 (q, J = 6.0 Hz, 1H) , 3.90-3.60 (m, 4H) , 3.02 (s, 12H) , 2.84 (s, 3H) .

Example 14 2- [3-acetoxy-1-oxopropyl] -3-methylbenzothiophene A suspension of 3.8 g (13.4 mmol) of 2-[(3-N- dimethylamino) -2-oxopropyl] -3-methylbenzothiophene and 1.1 g (13.4 mmol) of sodium acetate in 12 mL of acetic anhydride was heated at 80^s C for 30 min. The reaction was quenched with water (25 mL) and the mixture was stirred for 15 min and then extracted with dichloromethane (2 x 50 mL) . The combined organic phases were dried (MgS0 ) and evaporated to dryness. The crude reaction product was purified by column chromatography, to afford the title compound (1.1 g, 31%) and an elimination product: 2- ( l-oxoprop-2-enyl) -3- methylbenzothiophene (1.4 g, 52%). M.p. 99-100² C. ^XH NMR (CDC1₃) V.85 (m, 2H) , 7.55-7.35 (m, 2H) , 4.50 (t, J = 6.2 Hz, 1H) , 3.25 (t, J = 6.2Hz, 2H) , 2.75 (s, 3H) , 2.03 (s, 3H) . Example 15

N-Benzyl-N' -phenyl-N' - [3-oxo-3- ( 3 -methyl- benzothiophen-2-yl)propyl] urea a) 2- [3-phenylamino-l-oxopropyl] -3-methylbenzothiophene. The title product was obtained using the procedure described in Example 8b) , but using aniline. ¹H NMR (CDC1₃) : 7.85 (m, 2H) , 7.45 (m, 2H) , 7.17 (m,2H), 6.68 ( , 3H) , 4.15 (br s, 1H) , 3.63 (t, 2H) , 3.26 (t, 2H) , 2.77 (s, 3H) . b) N-Benzyl-N' -phenyl-N' - [3-oxo-3- (3 -methylbenzothiophen- 2 -yl) propyl] urea

To a solution of the product of step a) (0.025 mmol) in CHCI3 (1 mL) , was added benzylisocyanate (0.0375 mmol). The reaction mixture was stirred for 20 h. Then the excess of the benzyl isocyanate was scavenged with aminomethyl polystyrene (0.20 mmol). The title compound was isolated without further purification. ^XH NMR (CDC1₃) 7.85 (m, 2H) , 7.55-7.10 (m, 7H) , 4.61 (m, 1H) , 4.48 (m, 2H) , 4.18 (m, 2H) , 3.29 (m, 2H) , 2.72 (s, 3H) .

Example 16

N-Phenyl-N -phenyl-N' -[3-oxo-3-( 3-methyl- benzothiophen-2-yl)propyl] urea

The title product was obtained using the procedure described in Example 15b) but using as isocyanate phenyl isocyanate. The product was pure by t.l.c.

Example 17

N-3, 4-Dichlorophenyl-N' -phenyl-N'- [3-oxo-3- (3-methyl- benzothiophen-2-yl) propyl] urea The title product was obtained using the procedure described in Example 15b) but using as isocyanate 3,4- dichlorophenyl isocyanate. The product was pure by t.l.c. Example 18 (E) -3-Methyl-2- [2- (4-pyridyl) ethen-1-yl]benzothiophene a) 3-Methylbenzothiophene-2-carboxaldehyde

To a solution of 3-methylbenzothiophene (10 mmol, 1.0 eq) in THF (lOmL) was added at -78²C 1.1 eq. of nBuLi . After 30 min N,N-dimethylformamide (2.0 eq) was added and the mixture was warmed up to 0²C. The reaction was stirred for 3 h and then quenched with a saturated solution of NH₄C1 and extracted with AcOEt (3 x 20mL) . Yield 78%. ^XH NMR (CDC1₃) : 10.48 (s, 1H) , 7.91 (m, 2H) , 7.51 ( , 2H) , 2.82 (s, 3H) . b) (E) -3-Methyl-2- [2- (4-pyridyl) ethen-1-yl] benzothiophene To a mixture of the product of step a) (1.99 mmol) and

4-picoline (5.97 mmol) was added AcONa (3.98 mmol) in Ac₂0 (10 mL) . The mixture was heated at 140²C and stirred for 40 h. The reaction mixture was allowed to cool to room temperature and stirred with a 10% solution of NaCθ₃ for 30 min. The aqueous phase was extracted with CH₂C1₂ (3 x 20 mL) and the combined organic extracts were washed with 5% HC1 (50 mL) . After solvent elimination at reduced pressure, the residue was purified by chromatography (EtOAc-CH₂Cl₂ 1:1). Yield 53%. ^λE NMR (CDCI3) : 8.59 (d, J=6.4 HZ, 2H) , 7.79 (m, 1H) , 7.74 (d, J= 16.1 HZ, 1H) , 7.71 (m, 1H) , 7.50 (d, J= 6.4 Hz, 2H) , 7.40 (m, 2H) , 6.88 (d, J= 16.1 Hz, 1H) , 2.54 (s,

3H)

Example 19 3-Chloro-2- (2-pyridylmethylaminocarbonyl)benzothiophene

To a solution of 3-chlorobenzothiophene-2-carboxylic acid (1.66 mmol) in dry THF (2 mL) was added oxalyl chloride (4.98 mmol) and the mixture was heated under reflux for 1 h in an atmosphere of argon. The solvent and excess of reagent were then removed by evaporation, and the solid acid chloride (not isolated) was dissolved in dry THF (2.5 mL) and triethylamine (0.8 mL) and cooled at 0²C. Then, 2- pyridylmethylamine was added (2.49 mmol) and the mixture was stirred at room temperature for lh. Then, water was added (lOmL) and the mixture was extracted with CH₂C1 (3 x 10 mL) . The combined organic extracts were dried (Na₂S0₄) and evaporated to dryness giving an oil which was purified by chromatography (EtOAc-MeOH 4:1). Yield 83%. ^XH NMR (CDC1₃) : 8.66 (d, J= 5.4 Hz, 1H) , 8.60 (br s, 1H) , 7.90 (m, 2H) , 7.75 (dt, J= 7.8, 1.7 Hz, 1H) , 7.53 (m, 2H) , 7.40 (d, J= 7.8 Hz, 1H) , 7.28 (dt, J= 7.8, 1.7 Hz, 1H) 4.89 (d, J= 4.7 Hz, 2H) . ¹³C NMR (CDC1₃) : 160.6, 155.5, 148.9, 137.8, 136.9, 136.6, 132.8, 127.1, 125.1, 122.9, 122.6, 122.3, 121.8, 119.1, 45.0.

Example 20 3-Chloro-2- (3-pyridylmethylaminocarbonyl)benzothiophene

The title product was obtained using the procedure described in Example 19, but using as amine 3- pyridylmethylamine . Yield 68%. ^!H NMR (CDC1₃): 8.66 (d, J= 2.1 Hz, 1H) , 8.56 (dd, J= 4.7 , 1.7 Hz , 1H) , 7.86 (m, 2H) , 7.76 (dt, J= 8.0, 2.2 Hz, 1H) , 7.51 ( , 2H) , 7.31 (dd, J= 8.5, 4.8 Hz, 1H) 4.74 (d, J= 5.8 Hz, 2H) . ¹³C NMR (CDCI3): 161.0, 149.2, 137.9, 136.7, 135.5, 133.4, 132.4, 127.4, 125.4, 123.6, 123.1, 122.7, 119.0, 41.5.

Example 21 N,N-Dimethylaminoethyl 3-Methylbenzothiophene-2-carboxylate hydrochloride a) 3-Methylbenzothiophene-2-carboxylic acid To a solution of 3-methylbenzothiophene-2- carboxaldehyde in acetone (8 mL) at 0²C was added Jones' reagent (1.75 mL) . The mixture was stirred at 0²C for 2h and at room temperature for 2h. Then, water (20mL) and isopropanol (20mL) were added, followed by 0. IN KOH (to 34

pH=7) and then 0.5 HCl (to pH=l). The mixture was then extracted with AcOEt (2 x 20mL) , dried (Na₂S0₄) and evaporated. ^XH NMR (CDC1₃) : 13.39 (br s, 1H) , 8.05 (m, 2H) , 7.51 (m, 2H) , 2.71 (s, 3H) .

b) N,N-Dimethylaminoethyl 3-Methylbenzothiophene-2- carboxylate hydrochloride

The title compound was obtained as a white solid by reacting the product of step a) with N,N-dimethylethanol- amine by the procedure described in Example 19 to afford an oil, followed by treating the oil with a saturated solution of HCl in ether. ^XH NMR (D₂0) : 7.56 (m, 2H) , 7.24 (m, 2H) , 4.36 (t, J= 5.8 Hz, 2H) , 3.29 (m, 2H) , 2.73 (s, 6H) , 2.23 (s, 3H) . ¹³C NMR (D₂0) : 163.4, 143.2, 139.9, 139.3, 127.8, 124.7, 124.1, 123.9, 122.4, 59.3, 43.2, 12.5.

Example 22 N,N-Dimethylaminopropyl 3-Methylbenzothiophene-2-carboxylate hydrochloride The title compound was obtained using the procedure described in Example 21b) , but using N,N-dimethyl- propylamine, to afford an oil which was treated with a saturated solution of HCl in ether. ¹H NMR (D₂0) : 7.60 (m, 2H) , 7.28 (m, 2H) , 4.02 (m, 2H) , 3.02 (m, 2H) , 2.73 (s, 6H) , 2.26 (s, 3H) , 1.96 (m, 2H) . ¹³C NMR (D₂0) : 163.5, 141.5,

139.7, 139.2, 127.3, 125.2, 124.3, 123.5, 122.1, 62.2, 54.8, 42.7, 23.4, 12.4.

Example 23 N,N-Dimethylaminoethyl 3-Chlorobenzothiophene-2-carboxylate

The title compound was obtained by the procedure described in Example 21b) , but using 3-chlorobenzothiophene- 2-carboxylic acid and N,N-dimethylethanolamine . ¹H NMR (CDC1₃):7.87 (m, 1H) , 7.71 (m, 1H) , 7.41 (m, 2H) , 4.42 (t, J= 5.9 Hz, 2H) , 2.67 (t, J= 5.91 Hz, 2H) , 2.29 (s, 6H) . ¹³C NMR (CDC1₃) : 160.9, 138.4, 136.8, 127.9, 127.2, 123.6, 125.3, 123.6, 122.5, 63.6, 57.4, 45.7.

Example 24

N,N-Dimethylaminopropyl 3-Chlorobenzothiophene-2-carboxylate hydrochloride

The title product was obtained by the procedure described in Example 21b) , but using N,N-dimethylpropylamine to give an oil, which oil was then treated with a saturated solution of HCl in ether. ^XH NMR (D₂0) : 7.55 (m, 2H) , 7.25 (m, 2H) , 4.01 (t, J= 6.4 Hz, 2H) , 3.04 (t, J= 7.5 Hz, 2H) , 2.72, (s, 6H) , 1.95 (m, 2H) . ¹³C NMR (D₂0) : 162.1, 138.2, 135.7, 128.7, 125.7, 123.4, 122.8, 62.7, 54.9, 42.7, 23.2.

Example 25

2- [3- (4-Phenylpiperazin-l-yl) -1-oxopropyl] -3- methylbenzothiophene a) 2- (l-oxoprop-2-enyl) -3-methylbenzothiophene. The title compound was obtained as described in Example 14. Yield 52%. ^XH NMR (CDC1₃): 7.88 (m, 2H) , 7.47 ( , 2H) , 7.08 (dd, 1H) , 6.50 (dd, 1H) , 5.90 (dd, lh) , 2.79 (s, 3H) . b) 2- [3- (4-Phenylpiperazin-l-yl) -1-oxopropyl] -3- methylbenzothiophene To a solution of the product of step a) (0.05 mmol) in CHCI₃ (1 mL) was added 1-phenylpiperazine (0,075 mmol). The reaction mixture was stirred overnight. The excess of amine was scavenged with polystyrene isocyanate. The title compound was isolated without further purification. ¹H NMR (CDCI3) : 7.85 (m, 2H) , 7.46 (m, 2H) , 7.24 (m, 2H) , 6.95-6.75 (m, 3H) , 3.24 (m, 6H) , 2.95 ( , 2H) , 2.76 (s, 3H) , 2.70 ( , 4H) .

Example 26 2- [3- (4- [2-hydroxyethyl]piperazin-1-yl) -1-oxopropyl] -3- methylbenzothiophene

The title compound was obtained by the procedure described in Example 25b) using as amine, l-(2- hydroxyethyl )piperazine. The product was pure by t.l.c.

Example 27

2- [3- (4-Benzylpiperazin-l-yl) -1-oxopropyl] -3- methylbenzothiophene The title compound was obtained by the procedure described in Example 25b) using as amine, benzylamine. The product was pure by t.l.c.

Example 28 2- [3- (2-pyridylamino) -1-oxopropyl] -3-methylbenzothiophene

The title compound was obtained from the product of Example 8a) following the procedure described in Example 8b) and using 2-aminopyridine. ¹H NMR (CDC1₃): 8.10 (m, IH) ,

7.82 (m, 2H) , 7.42 (m, 3H) , 6.55 (m, IH) , 6.41 (m, IH) , 5.02 (br t, IH) , 3.83 (q, J= 7.1 Hz, 2H) , 3.88 (t, J= 7.1Hz, 2H) , 2.77 (s, 3H) . ¹³C NMR (CDCl₃): 194.9, 158.2, 147.9, 140.3, 139.9, 139.6, 137.2, 135.1, 127.6, 124.7, 124.1, 122.7, 112.7, 107.9, 42.1, 36.6, 13.9.

Example 29 2- (3-Dimethylamino-1-oxopropyl) -3-propylbenzothiophene hydrochloride a) 3-propylbenzothiophene

To a solution of 3-bromobenzothiophene (3.85 mmol) in anhydrous ether (20 ml), bis (1, 2 -diphenylphosphino) ethane- nickel (II) chloride (60 mg) in dry ether (25 ml) was added 37

and the suspension is stirred for 10-15 min. Then, a 2M solution in ether of propyl magnesium chloride (3.85 ml) was added dropwise. The reaction mixture turned dark and a mild exother developed. The solution was heated at reflux for 18h. The reaction mixture was then cooled and quenched with diluted hydrochloric acid. The organic phase was separated and washed with aqueous sodium bicarbonate and brine and the solvent was removed in vacuo to give an oil which was purified by chromatography (hexane) to yield the title compound (60%). b) 2-acetyl-3-propylbenzothiophene

To a solution of the product of step a) (1.3 mmol) in methylene chloride (6 ml), acetic anhydride (6.55 mmol) and boron trifluoride etherate (1.3 mmol) were added. The solution was heated at 80 ^eC for 3h and then was quenched with a saturated sodium bicarbonate solution and extracted with dichloromethane (3 X 20 ml) . The combined organic phases were dried (MgS0₄) and concentrated to dryness giving an oil which was purified by column chromatography (AcOEt/Hexane 1:4). (Yield 80%) ^-NMR (CDC1₃): 7.9-7.7 (m) , 7.4-7.3 (m) , 3.2 (t), 2.2 (s), 1.7-1.4 (m) , 0.9 (t) ppm. c) 2- (3-dimethylamino-l-oxopropyl) -3-propylbenzothiophene hydrochloride

The title compound was obtained as described in Example 7b from the product of step b) . ^-NMR (CDCI₃) : 7.9-7.8 (m) , 7.5-7.2 (m) , 3.3-3.06 (m) , 2.8 (t), 2.2 (s), 1.7-1.6 (m) , 1.0 (t) ppm.

Example 30 2- [3- (N-imidazolyl) - 1-oxopropyl] -3-butylbenzothiophene hydrochloride a) 3-Butylbenzothiophene

The title compound was obtained as described in Example 29a) using butyl magnesium chloride (Yield 90%) . 38

b) 2-acetyl-3-butylbenzothiophene

The title compound was obtained from the product of step a) using the procedure described in Example 29b) ^-NMR (CDC1₃): 7.9-7.8 (m) , 7.5-7.4 (m) , 3.3 (t) , 2.2 (s) , 1.7-1.4 ( ) , 0.9 (t) ppm c) 2- (3-dimethylamino-l-oxopropyl) -3-butylbenzσthiophene The title compound was obtained as described in Example

7b from the product of step b) . ^-NMR (CDC1₃) : 8.0-7.9 (m) , 7.6-7.4 (m) , 3.6 (s), 3.3 (t), 3.0 (s) , 1.7-1.4 (m) , 0.9 ( t ) ppm. d) 2- [3- (N-imidazolyl) - 1-oxopropyl] -3 -butylbenzothiophene hydrochloride

The title compound was obtained by the method of Example 7c) from the product of step c) . ¹H-NMR (CDCI₃) : 7.9-7.8 (m) , 7.6-7.4 (m) , 7.1-6.9 (m) , 4.4 (t), 3.4 (t), 3.3 (t), 1.7-1.4 (m) , 0.9 (t) ppm.

Example 31 2- [3- (N-Imidazolyl) -1-oxopropyl] -3-phenylbenzothiophene hydrochloride a) 3 -Phenyl benzothiophene

The title compound was obtained as described in Example 29 a), but using phenyl magnesium chloride. (Yield 69%) b) 2-Acetyl-3-phenylbenzothiophene The title compound was obtained from the product of step a) using the procedure described in Example 29b) . c) 2- (3-Dimethylamino-l-oxopropyl) -3-phenylbenzothiophene hydrochloride

The title compound was obtained as described in Example 7b) from the product of step b) . d) 2- [3- (N-imidazolyl) - 1-oxopropyl] -3-phenylbenzothiophene hydrochloride The title compound was obtained by the method of Example 7c) from the product of step c). ^Η-NMR (CDC1₃): 7.9 (m) , 7.6-7.0 (m) , 4.6 (broad s), 3.0 (broad s) ppm.

Example 32

2- (3-Dimethylamino-1-oxopropyl] -3-chlorobenzothiophene hydrochloride a) 3-chloro-2-benzothiophene(N,N-diethyl) carboxamide

A solution of 3 -chloro-2-benzothiophene carboxylic acid (2.35 mmol) and oxalyl chloride (12 mmol) in THF (20 ml) was heated under reflux for lh. Then the solvent was removed and the resulting white solid was dissolved in THF (10 ml) . Diethylamine (2.6 mmol) and triethylamine (2.35 mmol) were then added. The solution was heated under reflux for lh and then the solvent was concentrated. Ether was added and the triethylamine hydrochloride formed was filtered off and the filtrate concentrated to give an oil. The crude product was purified by chromatography (AcOEt/Hexane 1:1) to give 400 mg of the title compound (64%). ^Η-NMR (CDC1₃) : 7.9-7.8 (m) , 7.5-7.4 (m) , 3.7-3.6 (m) , 3.5-3.4 (m) , 1.3-1.1 (m) ppm. b) 2-acetyl-3-chlorobenzothiophene .

To a solution of the product of Step a) (0.63 mmol) in anhydrous ether (4 ml), a 1.6M solution of methyl lithium in ether (0.76 mmol) was slowly added at -78²C, under argon. After 2h at this temperature, the solution was quenched with a saturated solution of ammonium chloride and extracted with ether, dried and concentrated to give a crude product which was purified by column chromatography to yield 100 mg of a white solid (75%). ^-NMR (CDC1₃) : 8.0-7.9 (m) , 7.8-7.7 (m) , 7.6-7.4 (m) , 2.8 (s) ppm. c) 2- (3-Dimethylamino-l-oxopropyl] -3-chlorobenzothiophene hydrochloride

The title compound was obtained using the method described in Example 6 c) but heating under reflux at 110²C. ^-RMN (CDCI3) : 8.1-7.9 (m) , 7.7-7.5 (m) , 3.8 (t) , 3.6 (t) , 2.9 ( s ) ppm .

Example 33 2- (3-Dimethylamino-1-oxopropyl] -3-bromomethylbenzothiophene hydrochloride a) 3-Bromomethylbenzothiophene

A mixture of 3-methylbenzothiophene (6.75 mmol), N- bromosuccinimide (6.75 mmol) and aza-bis-isobutyronitrile (1.5 mmol) in carbon tetrachloride (15 ml) was heated under reflux for 9h. The suspension was then cooled and filtered. The filtrate was concentrated to dryness and the residue was triturated with methanol to yield a white solid (60%) . b) 2-acetyl-3-bromomethylbenzothiophene The title compound was obtained as described in Example 29b) using the product of step a) . c) 2- (3-dimethylamino-l-oxopropyl] -3-bromomethylbenzothiophene hydrochloride

The title compound was obtained from the product of step b) by the method of Example 6c). ^- MR (CDCI₃): 8.1(d), 7.9 (d) , 7.6 (m) , 5.4 (s), 4.8 (s), 3.6 (m) , 3.0 (s) ppm.

Claims

41

Claims:

Use of a compound of general formula:

in which:

R¹ represents a halogen atom, a (1-6C) alkyl, halo (1-6C) alkyl or (l-δC)alkylthio group, or a phenyl group which is unsubstituted or substituted by one or two substituents selected independently from a halogen atom, a (1-4C) alkyl group and a (1-4C) alkoxy group;

R² represents a hydrogen atom, a halogen atom, a (1-4C) alkyl group or a (1-4C) alkoxy group; Y represents COCHR³ , COO, CONH or CH=CH;

L represents a bond or (1-4C) alkylene; and Z represents :

(i) -NR⁴R⁵, in which each of R⁴ and R⁵ independently represents (1-4C) lkyl ;

(ii) a group of formula

in which R represents phenyl, phenyl (1-4C) alkyl or hydroxy ( 2-4C) alkyl ; (iii) a group of formula

in which R⁷ represents hydrogen or (1-4C) alkyl; (iv) -NHR⁸ in which R⁸ represents pyridyl or (CH₂)_nNR⁹R¹⁰ in which n is an integer of from 1 to 4 and R⁹ and R¹⁰ each independently represents (1-4C) alkyl ; (v) pyridyl (vi) a group of formula

in which A- represents an anion; (vii ) a group of formula

in which R represents phenyl, L represents a bond or (1-

4C)alkylene and R¹² represents phenyl which is unsubstituted or substituted by one or two substituents selected from a halogen atom, a(l-4C)alkyl group and a (1-4C) alkoxy group; or

(viii) OR¹³ in which R¹³ represents (1-4C) alkanoyl; or a pharmaceutically acceptable salt thereof, provided that when Y represents COO or CONH, L does not represent a bond, for the manufacture of a medicament for the treatment of a condition indicating treatment with a GluR6 antagonist. 43

2. Use as claimed in Claim 1, in which R¹ represents chlorine, methyl, ethyl, propyl, butyl, bromomethyl, or phenyl .

3. Use as claimed in Claim 1 or Claim 2, in which R² represents hydrogen.

4. Use as claimed in any one of Claims 1 to 3 , in which R³ represents a hydrogen atom, an ethyl group, a phenyl group or a group of formula -L^a-Z^a in which L^a represents methylene and Z^a represents dimethylamino.

5. Use as claimed in any one of Claims 1 to 4 , in which L represents a bond, methylene, ethylene or propylene.

6. Use as claimed in any one of Claims 1 to 5 , in which Z represents dimethylamino; 1- (4-phenyl )piperazinyl ; l-(4- benzyDpiperazinyl; 1- (4- (2-hydroxy) ethyl )piperazinyl; 1- imidazolyl; 1- (2-methyl) imidazolyl ; 1- (4-methyl) imidazolyl; 1- (5-methyl) imidazolyl; 2-pyridylamino; 3-pyridylamino; 4- pyridylamino; 2- (dimethylamino) ethylamino; 2-pyridyl; 3- pyridyl; 4-pyridyl; 4-aminopyridinium halide; 1,3- diphenylureido; 3 -benzyl-1-phenylureido; 3- (3, 4- dichlorophenyl) -1-phenylureido or acetoxy.

8. A method of antagonising the action of L-glutamate at GluR6 receptors in a warm blooded mammal requiring such treatment, which comprises administering to said mammal an effective amount of a compound of general formula : -

in which: R¹ represents a halogen atom, a (1-6C) alkyl, halo (1-6C) alkyl or (l-βC)alkylthio group, or a phenyl group which is unsubstituted or substituted by one or two substituents selected independently from a halogen atom, a (1-4C) alkyl group and a (1-4C) alkoxy group;

Y represents COCHR³ , COO, CONH or CH=CH;

R³ represents a hydrogen atom, a (1-4C) alkyl group, a phenyl group or a group of formula -L^a-Z^a in which L is as defined for L and Z^a is as defined for Z ;

L represents a bond or (1-4C) alkylene; and

Z represents :

(ii) -NR⁴R⁵, in which each of R⁴ and R⁵ independently represents (1-4C) alkyl;

(ii) a group of formula

in which R⁶ represents phenyl, phenyl (1-4C) alkyl or hydroxy (2-4C) alkyl; (iii) a group of formula

in which R⁷ represents hydrogen or (1-4C) alkyl; (iv) -NHR⁸ in which R⁸ represents pyridyl or (CH₂)_nNR⁹R¹⁰ in which n is an integer of from 1 to 4 and R⁹ and R¹⁰ each independently represents ( 1-4C) alkyl; (v) pyridyl (vi) a group of formula

in which A- represents an anion; (vii ) a group of formula

in which R¹¹ represents phenyl, L^b represents a bond or (1- 4C)alkylene and R¹² represents phenyl which is unsubstituted or substituted by one or two substituents selected from a halogen atom, a(l-4C)alkyl group or a (1-4C) alkoxy group; or (viii) OR¹³ in which R¹³ represents (1-4C) alkanoyl; or a pharmaceutically acceptable salt thereof, provided that when Y represents COO or CONH, L does not represent a bond. 9. A compound of general formula :-

in which:

R¹ represents a halogen atom, a (1-6C) alkyl, halo (1-6C) alkyl or (1-6C) alkylthio group, or a phenyl group which is unsubstituted or substituted by one or two substituents selected independently from a halogen atom, a(l-4C)alkyl group and a (1-4C) alkoxy group;

Y represents COCHR³, COO, CONH or CH=CH; 46

L represents a bond or (1-4C) alkylene; and

Z represents :

(i) -NR⁴R⁵, in which each of R⁴ and R⁵ independently represents (1-4C) alkyl; (ii) a group of formula

in which A- represents an anion; (vii) a group of formula

in which R represents phenyl, L^b represents a bond or (1-

(viii) OR¹³ in which R¹³ represents ( 1-4C) alkanoyl; or a pharmaceutically acceptable salt thereof, provided that : - (a) when Y represents COO or CONH, L does not represent a bond;

(b) when Y represents -CH=CH- and Z represents dimethylamino, R¹ does not represent an unsubstituted or substituted phenyl group; (c) when Y represents CONH and R¹ represents a halogen atom, Z does not represent a group of formula

(d) the compound of formula I is not selected from:-

2- [ (4-phenyl-l-piperazinyl) acetyl] -5-chloro-3- methylbenzo [b] thiophene ;

1- (5-chloro-3-methylbenzo[b] thien-2-yl] -3- [4- (phenylmethyl)

1-piperazinyl] -1-propanone;

1- (3, 5-dimethylbenzo [b] thien-2-yl] -3- [4- (phenylmethyl) -1- piperazinyl] -1-propanone; 3-chloro-N- [3- (2-ethyl-lH-imidazol-l-yl)propylbenzo [b] - thiophene-2-carboxamide;

3- (dimethylamino) propyl 3-chlorobenzo [b] thiophene-2- carboxylate; 48

2- (diethylamino) ethyl 3-chlorobenzo [b] thiophene-2- carboxylate;

2-dimethylamino) ethyl 3-chlorobenzo [b] thiophene-2- carboxylate; 3-chloro-N- [2- (4-phenyl-l-piperazinyl) ethyl]benzo [b] - thiophene-2-carboxamide;

3, 6-dichloro-N- [2- (4-phenyl-l-piperazinyl) ethyl] benzo [b] - thiophene-2-carboxamide; and

2- (3-dimethylamino-l-oxopropyl] -3-methyl-5-chloro- benzothiophene .

10. A compound as claimed in Claim 9, in which R¹ represents chlorine, methyl, ethyl, propyl, butyl, bromomethyl , or phenyl .

11. A compound as claimed in Claim 9 or Claim 10, in which R² represents hydrogen.

12. A compound as claimed in any one of Claims 9 to 11, in which R³ represents a hydrogen atom, an ethyl group, a phenyl group or a group of formula -L^a-Z^a in which L^a represents methylene and Z^a represents dimethylamino. 13. A compound as claimed in any one of Claims 9 to 12, in which L represents a bond, methylene, ethylene or propylene.

14. A compound as claimed in any one of Claims 9 to 13, in which Z represents dimethylamino; 1- ( 4-phenyl)piperazinyl ; 1- (4-benzyl)piperazinyl; 1- (4- (2-hydroxy) ethyl )piperazinyl ; 1-imidazolyl; 1- (2-methyl) imidazolyl; l-(4- methyl) imidazolyl; 1- (5-methyl) imidazolyl ; 2-pyridylamino;

3-pyridylamino; 4-pyridylamino; 2- (dimethylamino) ethylamino;

2-pyridyl; 3-pyridyl; 4-pyridyl; 4-aminopyridinium halide;

1, 3-diphenylureido; 3-benzyl-1-phenylureido; 3- (3, 4- dichlorophenyl) -1-phenylureido or acetoxy.

15. A compound as claimed in Claim 9, which is 2- [3- (4- pyridyl) amino-1-oxoproρyl] -3-methylbenzothiophene or a pharmaceutically acceptable salt thereof. 49

16. A process for the preparation of a compound as claimed in any one of Claims 9 to 15, which comprises: reacting a compound of formula

in which X represents a leaving atom or group, with the appropriate amine, or for a compound of formula I in which Z represents OR¹³, the appropriate anhydride; (b) reacting a compound of formula

III with an N,N-dimethylmethyleneammonium halide;

(c) for a compound of formula I in which Y represents COR³, R³ represents L-Z^a, L and L^a each represents ethylene and Z and Z^a each represents dimethylamino, reacting a compound of formula III with tetramethyldiaminomethane;

(d) for a compound of formula I in which Z represents a group of formula

reacting a compound of formula 50

IV with an isocyanate of formula

CN-L^bR¹²

V

(e) for a compound of formula I in which Y represents CH=CH, Z represents pyridyl and L represents a bond, reacting a compound of formula

VI with the appropriate methylpyridine;

VII or a reactive derivative thereof, with an amine of formula

HN-L-Z VIII (g) for a compound of formula I in which Y represents COOH, reacting a compound of formula VII or a reactive derivative thereof with a compound of formula 51

reacting a compound of formula

X with a compound of formula

XI followed, if desired, by forming a pharmaceutically acceptable salt.

17. A pharmaceutical formulation, which comprises a compound as claimed in any one of Claims 9 to 15, and a pharmaceutically acceptable carrier.